Cancers in the form of malignant tumors are the second leading cause of death in the United States after heart disease (U.S. Dept. of Health and Human Services, National Vital Statistics Reports, 58(19), May 20, 2010). Many cancers are characterized by an increase in the number of neoplastic cells originating from an initially normal tissue which subsequently propagate to form a tumor mass. With malignant tumors, neoplastic cells invade neighboring tissues ultimately leading to their spread via the blood or lymphatic system to lymph nodes and other locations distant from the site of the original tumor via a process called metastasis. Cancer manifests itself in a wide variety of forms, with each form characterized by varied degrees of invasiveness and aggressiveness.
NQO1 bioactivatable drugs are metabolized by the enzyme NQO1 in a futile manner to generate a series of cytotoxic factors, such as reactive oxygen species (ROSs) or quinone-based drug metabolites that cause damage to DNA, typically by alkylation. One such NQO1 bioactivatable drug, beta-lapachone (3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione; β-lap), is a naturally-occurring quinone obtained from the bark of the Lapacho tree (Tabebuia vellanedae), which is native to Central and South America. The anti-cancer activity of β-lap is due to two-electron reduction of β-lap mediated by NAD(P)H: quinone oxidoreductase (NQO1, DT-diaphorase) using NADH or NAD(P)H as electron sources (Pardee et al., Curr Cancer Drug Targets, 2002, 2(3):227-42). In cells that express NQO1, the β-lap molecule undergoes a futile cycle resulting in reactive oxygen species (ROS) generation leading to eventual DNA single-strand breaks, hyperactivation of poly(ADP-ribose) polymerase-1 (PARP-1), loss of NAD+ and ATP pools, and a unique pattern of cell death referred to as “programmed necrosis” or “necroptosis” (Blanco et al., Cancer Res. 2010, 70(10):3896-904; Bentle et al., J Mol Histol, 2006; 37:203-18). Necroptosis is a unique form of cell death that has attributes of both apoptosis (e.g., terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) positive and chromatin and nuclear condensation) and necrosis (e.g., caspase and energy independent) (Bentle et al., J Mol Histol, 2006; 37:203-18). However, not all cancer cells respond to treatment with β-lap (Bentle et al., Cancer Res., 2007, 67(14):6936-45) and its non-specific distribution can lead to low tumor concentrations and systemic toxicity (Ough et al., Cancer Biol Ther., 2005, 4(1):95-102).
Biomarkers are gene expression products measured in a tissue or specific cell type whose concentration, presence, or lack thereof can indicate the presence or seriousness of a disease state. For cancer, identification of tumor-associated biomarkers has in some cases permitted the specific targeting of cancer cells based on the differential relative expression of one or more particular biomarkers expressed by a cancer cell. However, even within tumors originating from the same tissue type, considerable variations can exist within gene expression patterns between individuals or between subpopulations of individuals suffering from identical forms of cancer. Indeed, genome-wide gene expression profiling has permitted the molecular characterization of intertumoral gene expression variability, demonstrating specific molecular signatures that reflect underlying pathogenic mechanisms and molecular features that may be associated with survival in individual subtypes of tumors (Alizedeh et al, 2000, Nature, 403:503-511). Identification of tumor subtypes is critical, as anti-cancer therapies that may be effective for the treatment of one subtype may not be similarly effective in treating other subtypes due to the consequences of variation in gene expression patterns.
Consequently, given the variability of individual gene expression within tumors of the same cancer type, there exists a need for biomarkers whose expression can be used to select individuals or subpopulations of individuals for a particular anti-cancer therapy, such as β-lap, and whose measurement can not only predict the likelihood that an individual with a particular tumor subtype will benefit from a particular anti-cancer therapy, but whose expression is also useful for selecting individuals or subpopulations of individuals for that specific anti-cancer therapy. Such diagnostic markers could be used to guide health care professionals involved in the treatment of an individual suffering from particular subtypes of malignant tumors originating from the same tissue. Diagnostic markers of this sort would also be useful to track prognosis following the initiation of treatment with a specific treatment, such as treatment with NQO1 bioactivatable drugs such as β-lap.
Throughout this specification, various patents, patent applications and other types of publications (e.g., journal articles) are referenced. The disclosure of all patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety for all purpose